Estimated glomerular filtration rate leads to higher drug dose recommendations in the elderly compared with creatinine clearance.

PURPOSE: The elderly are at risk for adverse drug events because of inappropriate dosing of renally eliminated medications. The purpose of this study was to evaluate differences in estimates of kidney function and recommended doses of select medications in the elderly using the Modification of Diet in Renal Disease (MDRD) or the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations compared with the Cockcroft-Gault (CG) equation. METHODS: Patients 65 years of age and older were included in this retrospective, observational analysis. Kidney function was estimated by CG, MDRD and CKD-EPI equations for all patients and by age category (65-69, 70-79, 80-89 and 90-100 years). Differences in estimates and dosing of allopurinol, enoxaparin, gabapentin, piperacillin/tazobactam and sulfamethoxazole/trimethoprim using the MDRD and CKD-EPI compared with the CG were assessed. RESULTS: In the 4160 patients (98% male, mean age 74 ± 7 years), the MDRD and CKD-EPI estimates were significantly higher than CG estimates for all patients and by age category (p < 0.001). Dosing discordance was predominantly because of a higher dose recommended by MDRD and CKD-EPI estimates compared with CG. Discordance was highest with gabapentin (27%), the medication with the greatest number of dosing stratifications by estimated kidney function, and increased by 66% from the youngest to the oldest age category. CONCLUSIONS: Until newer equations are used uniformly to develop dosing nomograms, it is prudent to adopt a process for drug dosing in the elderly that is more conservative than eGFR based dosing, but that considers the potential for underestimating kidney function with the CG equation.

P-REX1 creates a positive feedback loop to activate growth factor receptor, PI3K/AKT and MEK/ERK signaling in breast cancer.

Phosphatidylinositol 3-kinase (PI3K) promotes cancer cell survival, migration, growth and proliferation by generating phosphatidylinositol 3,4,5-trisphosphate (PIP3) in the inner leaflet of the plasma membrane. PIP3 recruits pleckstrin homology domain-containing proteins to the membrane to activate oncogenic signaling cascades. Anticancer therapeutics targeting the PI3K/AKT/mTOR (mammalian target of rapamycin) pathway are in clinical development. In a mass spectrometric screen to identify PIP3-regulated proteins in breast cancer cells, levels of the Rac activator PIP3-dependent Rac exchange factor-1 (P-REX1) increased in response to PI3K inhibition, and decreased upon loss of the PI3K antagonist phosphatase and tensin homolog (PTEN). P-REX1 mRNA and protein levels were positively correlated with ER expression, and inversely correlated with PI3K pathway activation in breast tumors as assessed by gene expression and phosphoproteomic analyses. P-REX1 increased activation of Rac1, PI3K/AKT and MEK/ERK signaling in a PTEN-independent manner, and promoted cell and tumor viability. Loss of P-REX1 or inhibition of Rac suppressed PI3K/AKT and MEK/ERK, and decreased viability. P-REX1 also promoted insulin-like growth factor-1 receptor activation, suggesting that P-REX1 provides positive feedback to activators upstream of PI3K. In support of a model where PIP3-driven P-REX1 promotes both PI3K/AKT and MEK/ERK signaling, high levels of P-REX1 mRNA (but not phospho-AKT or a transcriptomic signature of PI3K activation) were predictive of sensitivity to PI3K inhibitors among breast cancer cell lines. P-REX1 expression was highest in estrogen receptor-positive breast tumors compared with many other cancer subtypes, suggesting that neutralizing the P-REX1/Rac axis may provide a novel therapeutic approach to selectively abrogate oncogenic signaling in breast cancer cells.

Cerebral vascular response to moderate blood loss: modification by hypertension.

To study the effect of non-hypotensive hemorrhage on cerebral blood flow in normo- and hypertensive states, chloralose anesthetized cats were subjected to graded blood loss (5 ml/kg) every 30 min. Cerebral blood flow was measured using radiolabelled microspheres or H2 clearance. Hypertension was produced by infusion of phenylephrine to a diastolic blood pressure of 100 mm Hg. Control animals suffered no net blood loss. PCO2 was between 28 and 32 mm Hg for all groups over the entire experiment. In normotensive cats, cerebral blood flow increased following withdrawal of 10 ml/kg of blood. In hypertensive cats, cerebral blood flow increased after withdrawal of 20 ml/kg of blood. These findings were consistent for all brain regions examined. Animals without blood loss, whether normo- or hypertensive showed no consistent change in cerebral blood flows. Possible explanations for these findings, particularly neurally mediated responses, are discussed.

The favorable effect of early parenteral feeding on survival in head-injured patients.

This prospective randomized controlled clinical trial compares the effects of early parenteral nutrition and traditional delayed enteral nutrition upon the outcome of head-injured patients. Thirty-eight head-injured patients were randomly assigned to receive total parenteral nutrition (TPN) or standard enteral nutrition (SEN). Clinical and nutritional data were collected on all patients until death or for 18 days of hospitalization. Survival and functional recovery were monitored in survivors for 1 year. Of the 38 patients, 18 were randomized to the SEN group and 20 to the TPN group. Demographically, the two groups of patients were similar on admission. There was no significant difference in the severity of head injury between the two groups as measured by the Glasgow Coma Scale (p = 0.52). The outcome for the two groups was quite different, with eight of the 18 SEN patients dying within 18 days of injury, whereas no patient in the TPN group died within this period (p less than 0.0001). The basis for the improved survival in the TPN patients appears to be improved nutrition. The TPN patients had a more positive nitrogen balance (p less than 0.06), and a higher serum albumin level and total lymphocyte count. More adequate nutritional status may have improved the patients' immunocompetence, resulting in decreased susceptibility to sepsis. The data from this study strongly support the favorable effect of early TPN on survival from head injury.

Failure of prophylactically administered phenytoin to prevent early posttraumatic seizures.

A randomized double-blind placebo-controlled study was carried out to determine whether phenytoin administered soon after injury lessens the incidence of epilepsy in the 1st week after severe head trauma. In this study, 244 patients were randomized into either a phenytoin or placebo group. The patients in the phenytoin group were administered phenytoin intravenously or intramuscularly within 24 hours of hospital admission. Patients in the placebo group received intravenous or intramuscular diluent. The patients were switched from parenterally administered phenytoin or placebo as soon as oral doses could be tolerated. Over 78% of the phenytoin patients had plasma concentrations of at least 10 micrograms/ml at 1, 3, and 7 days after injury. There was no significant difference in the percentage of patients having early seizures in the treated and placebo groups (p = 0.99). There was no significant difference in the interval from injury to first seizure between the treated and placebo groups (p = 0.41). The early administration of phenytoin did not lessen the occurrence of seizures in the 1st week after head injury. Since the effectiveness of seizure prophylaxis has not been established, the authors suggest that anticonvulsant drugs be administered only after an early seizure has occurred.

Failure of prophylactically administered phenytoin to prevent late posttraumatic seizures.

This randomized double-blind placebo-controlled study was undertaken in a series of 179 patients to determine whether phenytoin administered soon after head injury lessens the incidence of late posttraumatic epilepsy. When delayed hypersensitivity to phenytoin developed, the patient was switched to phenobarbital. The patients were followed for 18 months to detect the occurrence of seizures and to serially measure plasma phenytoin concentrations. There was no significant difference in the percentage of patients having late seizures in the treated and placebo groups (p = 0.75). The time between injury and seizures did not significantly differ between the two groups. The results provide no support for the continued use of phenytoin in the low therapeutic range for prophylaxis against late posttraumatic seizures. It cannot be concluded that higher phenytoin plasma concentrations and higher compliance rates than obtained in this study would not have significantly decreased the occurrence of late posttraumatic epilepsy. The finding that no patient with a phenytoin plasma concentration of 12 microgram/ml or higher had a seizure raises the question of whether phenytoin in blood concentrations in higher therapeutic ranges might lessen the occurrence of posttraumatic epilepsy, and should be studied further. Posttraumatic epilepsy is a major public health problem deserving a large cooperative trial to determine if phenytoin at higher blood levels than obtained in this study, or other currently available or newly developed drugs, can prevent the occurrence of posttraumatic epilepsy.

Alterations in the cellular immune response of patients with cerebral glioma, benign intracranial tumour, and spontaneous subarachnoid haemorrhage measured in vitro by the leucocyte migration inhibition test.

Leucocyte migration inhibition in response to ubiquitous antigens was studied in 104 patients as an in vitro indicator of cell-mediated immunity. Patients with cerebral glioma, benign intracranial tumours, and subarachnoid haemorrhage demonstrated impaired inhibition of leucocyte migration compared with control subjects. The greatest impairment occurred in patients with subarachnoid haemorrhage, while the least impairment was seen in patients with glioma. Significant rises in inhibition of leucocyte migration in response to antigen preparations from glioma and normal brain were seen in the early post-operative period in patients with glioma and subarachnoid haemorrhage. Impaired cellular immunity, together with sensitivity of lymphocytes to brain-derived antigens, are features of cerebral disease in general and not specific for glioma.

Early prediction of outcome in head-injured patients.

The relationship between Glasgow Coma Scale (GSC) scores obtained during the 1st week after head injury and outcome at 1 year was analyzed in 170 patients. Seventy-two of 76 patients with initial GCS scores of 3 or 4 lived, and only one had a favorable outcome. Favorable and unfavorable outcomes were almost equally divided when the initial GCS scores were in the intermediate range of 5, 6, or 7. No patients with an initial GCS score in this intermediate range that subsequently worsened had a favorable outcome, while over 80% of those improving to a score higher than 7 had a favorable outcome. Only 12% of those persisting with a score of 5, 6, or 7 for 1 week had favorable outcome. Outcome predictions using the multiple logistic model were made for this intermediate group of patients based on GCS scores and data on midline shift derived from computerized tomography (CT). The patients with initial scores of 5, 6, or 7 with midline shifts of less than 4.1 mm on initial CT scanning had a significantly higher favorable outcome rate compared with patients with a larger shift. However, outcome prediction made by combining shift data and initial GCS scores are not significantly more accurate than predictions based solely on initial GCS scores. Combining 48-hour GCS scores and shift data significantly improves predictive accuracy based only on coma scores. The data obtained by combining GCS scores at 72 hours and 1 week and shift data is marginally significant for improving accuracy of outcome predictions. It is concluded that GCS scores and shift data are highly accurate indicators of outcome in head-injured patients.

Prospective randomized study of therapy in cerebrospinal fluid shunt infection.

Thirty patients who met the rigid criteria for a prospective randomized study of cerebrospinal fluid (CSF) shunt infections underwent therapy with the three currently advocated treatment modalities to determine the efficacy of each form of therapy. Ten patients (Group A) underwent shunt removal and, in addition to receiving systemic antibiotics, were treated by either external ventricular drainage or intermittent ventricular taps for decompression and antibiotic administration; 10 patients (Group B) were treated by removal and immediate replacement of the shunt and intrashunt antibiotic therapy; and 10 patients (Group C) received antibiotics without removal or replacement of the shunt. All patients were given intravenous and intraventricular antibiotics as follows: in Group A, antibiotics were given by both the intravenous and the intraventricular routes for a minimal period of 7 days; in Group B, intravenous antibiotics were administered for a minimal period of 3 weeks and twice daily intraventricular antibiotics were given for a minimal period of 2 weeks; in Group C, intravenous antibiotics were administered for a minimal period of 3 weeks and twice daily intraventricular antibiotics were given for a minimal period of 2 weeks. In all patients, CSF was obtained from the shunt and cultured 48 hours after the cessation of antibiotic therapy, and the cultures were repeated within 4 months of the completion of treatment. All patients in Group A and 9 of 10 patients in Group B were treated successfully. They were clinically asymptomatic, and cultures after treatment were sterile. However, only 3 patients in Group C responded to treatment. The remaining patients of Group C had persistent infections requiring additional therapy. The mean follow-up of the study group was 23 +/- 14 (SD) months. The mean hospitalization time for the study group was 33 +/- 21 days; the hospitalization time was 24.7 +/- 17 days for Group A alone, 32.7 +/- 8 days for Group B, and 47 +/- 37 days Group C.

Cervical dermal sinus and intramedullary spinal cord abscess: case report.

Congenital dermal sinuses in the cervical region are rare. A case report is presented in which the persistent anomaly led to formation of an intramedullary spinal cord abscess. The clinical presentation, radiological diagnosis, and surgical management are discussed.

The effect of high dose dexamethasone in children with severe closed head injury. A preliminary report.

Out of a total 157 hospitalized head-injured children, twelve years of age and under, fifteen were considered to be severe, three of whom died within 72 hours of admission. Nine children with closed head injuries who were in coma for at least 24 hours (did not open eyes, speak, or follow commands), with absent or impaired oculocephalic reflex, impaired pupil reactivity to light, and who were decerebrating for at least twelve hours, were studied. Five were given high dose dexamethasone therapy (1 mg/kg) within six hours of injury, repeated at six hours, and then maintained at 1 mg/kg/day for eight days, and four either received none or were treated with a low dose regimen (0.25 mg/kg/day). In those receiving high dose therapy, intracranial pressure waves were noticeably less, peak intracranial pressure was lower, and intensive care and hospital stay were shorter. It was also noted that in the high dose therapy group spontaneous eye opening and speech returned sooner, and all were considered to have returned to their premorbid status by six months following injury. Of the no steroid or low dose group, one died, and of the remainder at six months one was aphasic and still decerebrating, another was aphasic and severely handicapped, and the third returned to school seven months after injury.

Cerebrospinal fluid antibiotic concentrations in ventricular shunt infections.

The concentration of antibiotic in cerebrospinal fluid was measured during treatment of seven children with infected ventricular shunts. Antibiotics were administered via the ventricular shunt or through an external ventricular drain. 53 CSF samples were obtained 7-19 h after antibiotic administration. Wide variation in cerebrospinal fluid antibiotic concentration occurred from patient to patient following either route of administration. For optimal management of shunt infections, we recommend periodic assessment of antibiotic concentration or activity in ventricular fluid and determination of the minimum inhibitory concentration of antibiotic required for each pathogen.

Nationwide residues of mercury, lead, cadmium, arsenic, and selenium in starlings, 1973.

Starlings (Sturnum vulgaris) collected in 1973 at 51 sites throughout the continental United States were analyzed for mercury, lead, cadmium, arsenic, and selenium. All samples contained detectable levels of these elements. In general, residues were low: mercury residues ranged from less than 0.01 to 0.20 ppm; lead, from less than 0.10 to 3.20 ppm; cadmium, from less than 0.05 to 0.20 ppm; arsenic, from less than 0.05 to 1.40 ppm; and selenium, from 0.10 to 1.10 ppm. There was a significant overall decline in mercury and lead residues in starlings since 1971, and a significant increase in arsenic residues. Lead residues were significantly higher in starlings from urban areas than from rural areas.

Mercury, arsenic, lead, cadmium, and selenium residues in fish, 1971-73--National Pesticide Monitoring Program.

As part of the National Pesticide Monitoring Program, the Fish and Wildlife Service, U.S. Department of Interior, analyzed selected fish samples from 100 monitoring stations for residues of mercury, arsenic, lead, cadmium, or selenium in 1971-73. At most stations, detectable residues of all metals were present in more than 95 percent of the composite samples. Fishes with mercury residues exceeding 0.5 mg/kg wet weight in the whole fish were mainly predators. Fishes with residues of arsenic, lead, cadmium, and selenium exceeding 0.5 mg/kg included predatory and nonpredatory species. The number of composite samples in which residues of these elements exceeded 0.5 mg/kg decreased from 1971 to 1973, whereas the percentage of samples with detectable residues increased slightly. Only selected samples were analyzed in 1973; therefore, these figures should be used only cautiously as trend data. Species of fish collected varied considerably between geographic regions but were similar from year to year within each region.